SOX9 reprograms endothelial cells by altering the chromatin landscape.

Autor:	Fuglerud BM; Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.; Department of Biosciences, University of Oslo, 0316 Oslo, Norway., Drissler S; Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada.; Cell and Developmental Biology Program, University of British Columbia V6T 1Z3, Vancouver, British Columbia, Canada., Lotto J; Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada.; Cell and Developmental Biology Program, University of British Columbia V6T 1Z3, Vancouver, British Columbia, Canada., Stephan TL; Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada.; Cell and Developmental Biology Program, University of British Columbia V6T 1Z3, Vancouver, British Columbia, Canada., Thakur A; Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada., Cullum R; Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada., Hoodless PA; Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.; Cell and Developmental Biology Program, University of British Columbia V6T 1Z3, Vancouver, British Columbia, Canada.; School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2022 Aug 26; Vol. 50 (15), pp. 8547-8565.
DOI:	10.1093/nar/gkac652
Abstrakt:	The transcription factor SOX9 is activated at the onset of endothelial-to-mesenchymal transition (EndMT) during embryonic development and in pathological conditions. Its roles in regulating these processes, however, are not clear. Using human umbilical vein endothelial cells (HUVECs) as an EndMT model, we show that SOX9 expression alone is sufficient to activate mesenchymal genes and steer endothelial cells towards a mesenchymal fate. By genome-wide mapping of the chromatin landscape, we show that SOX9 displays features of a pioneer transcription factor, such as opening of chromatin and leading to deposition of active histone modifications at silent chromatin regions, guided by SOX dimer motifs and H2A.Z enrichment. We further observe highly transient and dynamic SOX9 binding, possibly promoted through its eviction by histone phosphorylation. However, while SOX9 binding is dynamic, changes in the chromatin landscape and cell fate induced by SOX9 are persistent. Finally, our analysis of single-cell chromatin accessibility indicates that SOX9 opens chromatin to drive EndMT in atherosclerotic lesions in vivo. This study provides new insight into key molecular functions of SOX9 and mechanisms of EndMT and highlights the crucial developmental role of SOX9 and relevance to human disease. (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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